The United States Pharmacopeia and the National Formulary
Pharmacopeia Chapter 1: Introduction to Drugs and Pharmacy Pharmakon: drug Poiein: make Drug Agent intended for use in the diagnosis, mitigation, Any recipe or formula or other standars required to treatment, cure or prevention of disease in humans make or prepare drug or animals (FDCA, 1938) Lititz Pharmacopeia Pharmacology First American pharmacopeia Nature and mechanism of action of the drug on the Published in 1778 at Lititz, Pennsylvania biologic system 32-page booklet, 84 internal and 16 external drugs [The Heritage of Pharmacy] and preaparations Practice of drug therapy was from experience Lyman Spalding Early people believed illnesses were caused by Father of USP demons or evil spirits in the body Proposed for a convention in 4 geographic districts People performed incantations, the application of United States Pharmacopeial Convention noisome materials and the administration of specific Revise USP every 10 years herbs or plant materials 1940 meeting: revise the USP every 5 years The First Apothecary 1830 and 1840: pharmacists were invited Pharmakon (Gk.): charm or drug that can be used 1850: full membership of pharmacists for good or for evil USP Knowledge of drug and their application to disease First published on December 15, 1820 in English and has always meant power Latin Early Drugs 217 drugs Ebers Papyrus American Pharmaceutical Association (APhA) 60 ft. long, a foot wide 1852 16th century BC National Formulary of Unofficial Preparations Founded by Georg Ebers Formulary containing many f the popular drugs and 800 formulas, 700 drugs formulas denied administration to the USP Introduction of the Scientific Viewpoint Changed to National Formulary on June 30, 1906 Hippocrates when President Theodore Roosevelt signed into law Introduction of scientific pharmacy and medicine USP XX and NF XV Rationalized medicine, systemized medical USP: volume; NF: sections knowledge, and put the practice of medicine on a USP 23-NF 18 high ethical plane o Became official in 1995 Hippocratic oath of ethical behavior USP Pharmacists Pharmacopeia Pharmakon beame for good only To address the needs of pharmacist practioners Father of Medicine Products Dioscorides Manufactured drugs First to deal with Botany Preparations De Materia Medica Compounded drugs Father of Botany USP and NF Monographs Claudius Galen Adopt standards for drug substances, pharmaceutical Galenic pharmacy ingredients and dosage forms reflecting the best in Galens Cerate, cold cream the current practices of medicine and pharmacy Emperor Fredrick II Official parts of a monograph Had a decree, which separated pharmacy from o Official title (generic or nonproprietary medicine in 1240 AD name) Aureolus Theophrastus Bombastus von Hohenheim o Graphic or structural formula Aka Paracelsus o Empirical formula Transformation of pharmacy from a profession based o Molecular weight primarily on botanical science to one based on o Established chemical names chemical science o Chemical Abstracts Service (CAS) registry Father of Toxicology number Early Research USP Drug Research and Testing Laboratory Karl Wilhelm Scheele o Provides direct laboratory assistance to the Discovered lactic acid, citric acid, ocalic acid, tartaric USP and NF acid, arsenic acid and oxygen o Main functions: evaluation of USP reference Identified glycerin standards and evaluation and development Invented new methods of preparing calomel and of analytical methods Other Pharmacopeias benzoic acid Homeopathic Pharmacopeia of the United States (HPUS) Friedrich Sertuner Used by law enforcement agencies that must ensure Isolation of morphine from opium the quality of homeopathic drugs Joseph Caventou and Joseph Pelletier Homeopathy Isolated quinine and cinchonine from chinchona o Coined by Samuel Hahnemann Isolated strychnine and brucine from nux vomica o Homoios = similar Joseph Pelletier and Pierre Robiquet o Pathos = disease Isolated caffeine o Law of similars, like cures like Pierre Robiquet International Pharmacopeia (IP) Separated codeine from opium Published by WHO Intended as a recommendation to a national No risk to animal reproduction studies pharmacopeial revision committees to modify their No adequate and well-controlled studies in pregnant pharmacopeias women International Organization for Standardization Category C International consortium of representative bodies Animal reproduction studies have shown an adverse constituted to develop and promote uniform or effect on the fetus harmonized international standards Category D Quality assurance (QA), quality control (QC), detectin There is positive evidence of human fetal risk of defective products, quality management (WM) Black Box Warning [Drug Regulation Control] Strongest labeling requirements for high-risk Food and Drug Act of 1906 medicines First federal law in the US designed to regulate drug All anti-depressant medications products Most serios warning Required drugs marketed interstate to comply with Ads are not allowed their caimed standards Drug Listing Act of 1972 Enacted to provide the FDA with the legislative authority to compile a list of marketed drugs to assist in the enforcement of federal laws [The Federal Food, Drug and Cosmetic Act of 1938] Drug Price Competition and Patent Term Restoration Act of Prohibits the distribution and use of any new drug or 1984 drug product without prior filing of a new drug Changes to speed the FDA approval of generic drugs application (NDA) and approval of the FDA and the extension of patient life for innovative new Required drugs to be safe for human use but did not drugs require it to be efficacious Prescription Drug Marketing Act of 1987 Durham-Humphrey Amendment of 1952 Established new safeguards on the integrity if the Prescriptions for legend drugs may not be refilled nations supply of prescription drug without the consent of the prescriber Dingell Bill or Drug Diversion Act Refill status was further regulated with the passage Intended to reduce the risks of adultered, of the Drug Abuse Amendments of 1965 and misbranded, repackaged or mislabeled drugs Comprehensive Drug Abuse Prevention and Control entering the legitimate marketplace through of 1970 secondary sources Kefauver-Harris Amendments of 1962 Reimportation, Sales restrictions, Distribution of To ensure a grater degree of safety for approved samples, Wholesale distributors drugs and manufacturers were now required to prove Dietary Supplement Health and Education Act of 1994 a drug to be both safe and effective Forbids manufacturers or distributors of products Sponsor of a new drug is now required to file an (vitamins, supplements) to make any advertising or investigational new-drug application (IND) before it labeling clams that the use of the product can can be tested on humans prevent or cure a specific disease Comprehensive Drug Abuse Prevention and Control Act of The FDA and the Food and Drug Administration Modernization 1970 Act of 1997 To consolidate and codify authority over drugs of FDAs mission: to protect the public health against abuse in a single statue risks associated with the production, distribution and Schedule I sale of food and food additives, human drugs and o Drugs with no accepted medical use biologicals o Substances with high potential of abuse Enacted to streamline FDA policies and to codify o Heroin, LSD, mescaline, peyote, manu of the agencys newer regulations methaqualone, marijuana Center for the Evaluation and Research (CDER) and Schedule II Center for Biologics Evaluation and Research (CBER) o Drugs with accepted medical uses and a Federal Register (FR) and Code of Federal Regulations (CFR) high potential for abuse, may lead to severe Provide the most definitive information on federal psychologic or physical dependence laws and regulations pertaining to drugs o Morphine, cocaine, methamphetamine, Drug Product Recall amobarbital A drug may be recalled if it presents a threat or Schedule III potential threat to consumer safety o If abused, it may lead to moderate Voluntary recall: manufacturer recalls the drug psychologic or physical dependence Class I o Specified quantities of codeine, o Will cause serious adverse health hydrocodone consequences or death Schedule IV Class II o Low potential for abuse, may lead to low o May cause temporary or medically psychologic or physical dependence reversible adverse health consequences o Specified quantities of diphenoxin, Class III diazepam, oxazepam o Not likely to cause adverse health Schedule V consequences o Specified quantities of dihydrocodeine, [The Pharmacists Contemporary Role] diphenoxylate The Mission of Pharmacy FDA Pregnancy Categories to serve society as the profession responsible for Category X the appropriate use of medications, devices and Strongest services to achieve optimal therapeutic outcomes May be implicated as a teratogen and the risk benefit Pharmacy is the health profession that concerns ratio does not support the use of the drug itself with the knowledge system that results in the Category A discovery, development and use of medication and No risk in to the fetus medication information in the care of patients. Category B Medications Manipulation of proteins within the cells of lower o Refers to legend and nonlegend agents used animals in the diagnosis treatment, prevention and Human insulin, human growth hormone, hep B cure of disease vaccine, epoetinalpha and interferon Devices Recombinant DNA o Equipment, process, biotechnological Manipulation of proteins within the cells of higher entities, diagnostic agents animals Services Used in home pregnancy testing products o Patient, health professional and public Human Gene Therapy education services Used to prevent, treat, cure, diagnose or mitigate human diseases caused by genetic disorders Definition of Pharmaceutical Care AT CG component of pharmacy practice which entails the Gene Therapy direct interaction of the pharmacist with the patient Medical intervention base on the modification of the for the purpose of caring for that patients drug- genetic material of living cells related needs Ex vivo: outside the body Patient-centered In vivo: within in the body Goal: to optimize the patients health-related quality Goal Drug of life and achieve positive clinical outcomes Would produce the specifically desired effect, be Pharmacists should be administered by the most desired dosage route o A problem solver Methods of Drug Discovery o Able to achieve health outcomes through Random/Untargeted Screening effective medication use Testing of large number of synthetic organic o Able to collaborate with others compounds or substances of natural origin o Life-long learner Used initially to detect an unknown activity of the The Omnibus Budget Reconciliation Act of 1990 test compound or substance Established a requirement for each state to develop Non-random/Targeted Screens and mandate DUR programs to improve the quality Determine the specific activity or a of pharmaceutical care compound/substance Required patient counseling Biostaysis Used to differenciate the effect and potency of the Chapter 2: New Drug Development and Approval test agent Process High-throughput Screening Capable of examining 15,000 chemical compounds a Treatment IND week For orphan drugs Molecular Modification Targeted to patients who have rare diseases Chemical alteration of a known and previously Supplemental New Drug Application (SNDA) characterized organic compound for the purpose of For certain changes in a previously approved NDA, enhancing its usefulness as a drug Mechanism-based drug design such as labeling or formulation change Molecular modification to design a drug that Abbreviated New Drug Application (ANDA) interferes specifically with the known or suspected Used to gain approval to market a duplicate of a biochemical pathway or mechanism of a disease process product Biologics Licensing Application (BLA) Enalaprilat (enalapril), ranitidine, sertraline (for Biologic products (human blood products and depression) Molecular graphics vaccines) Investigational New Animal Drug Application (INADA) Use of computer graphics to represent or manipulate New Animal Drug Application (NADA) the structure of the drug molecule Supplemental New Animal Drug Application (SNADA) Lead Compound [Drug Discovery and Drug Design] Prototype chemical compound that has a Alexander Fleming fundamental desired biologic or pharmacologic Penicillin activity International Conference on Harmonization Finasteride Fosters multinational drug approvals Prodrugs Sources of New Drugs A compound that requires metabolic Serendipity biotransformation after administration to produce the By accident desired pharmacologically active compound Reserpine Conversion of an inactive prodrug to an active Tranquilizer and hypotensive agent compound occurs through enzymatic biological Rauwolfia serpentine cleavage Periwinkle May be designed for solubility, absorption, Vinca rosea biostability and prolonged release o Absorption: a drug may be made more Treatment of diabetes mellitus water or lipid soluble Antitumor capabilities o Biostability: could result in site-specific Paclitaxel action (dopamine&levodopa) Ovarian cancer o Prolonged release: may extend therapeutic Semisynthetic drugs activity New structures from modified plant constituents FDAs Definition of a New Drug Recombinant DNA Any drug that is not recognized as being safe and Most fundamental effective in the conditions recommended for its use Genetic materials can be transplanted from higher species into a lowly bacterium (gene-splicing) Combination of 2 or more drugs or a change in the [Early Formulation Studies] usual proportions of drugs Preformulation Studies A proposed new use, new dosage schedule, new Drug solubility route of administration or new dosage form Poor soluble compounds (less than 10 mg/mL Drug Nomenclature aqueous solubility) C16H19N3O5Sx3H2O (amox) Partition coefficient Name must reveal every part of the compounds Drug molecules must first cross a biologic membrane molecular structure of protein and lipid Non-proprietary/Generic name: shortened name Measure of its distribution in a lipophilic-hydrophilic phase system and indicates its ability to penetrate [Biologic Characterization] biologic multiphase systems Cell cultures Dissolution rate Used to screen toxicity before progressing to whole- Speed at it which a drug substance dissolves in a animal testing medium Computer models Physical form Help predict the properties of substances and their Reducing particle size = absorption is increased probable actions in living systems Stability Pharmacology Durations and environments of light and air and pharmaco = drugs packaging is essential Science concerned with drugs, their sources, Initial Product Formulation and Clinical Trial Materials appearance, chemistry, action and uses Initial product is formulated using the information Pharmacodynamics: study of biochemical and gained during the preformulation studies physiologic effects of drugs and their mechanism of Phase 1 studies action Capsules are employed containing the active Pharmacokinetics: deals with the absorption, ingredient alone distribution, metabolism/biotransformation and Phase 2 studies excretion (ADME) of drugs Final dosage form is selected Clinical pharmacology: the study of the effects and Clinical supplies or clinical materials actions of drugs in humans Comprise all dosage formulation used in the clinical Whole-animal studies are used to evaluate the evaluation of a new drug pharmacologic effects of the agent on specific organ Blinded studies systems Controlled studies Primary objective of animal studies: to obtain basic At last one of the parties does not know which information on the drugs effects that may be used to product is being administered predict safe and effective use in humans [The Investigational New Drug Application] Drug Metabolism Sponsor of a new drug must file an IND before the Bodys means of transforming nonpolar drug drug may be given to human subjects molecules into polar compounds Sponsor must delay the use of drug in human subject First-pass effect: rapid drug metabolism for not less than 30 days ADME studies: performed through the timely Clinical hold is issued when there is concern that collection and analysis of urine, blood and fecal human subjects will be exposed to unreasonable and samples and through a careful examination of animal significant risk of illness or injury tissues and organs through autopsy The Clinical Protocol Toxicology Purpose and objectives of the study Deals with the adverse or undesired effects of drugs Estimate number of patients involved Acute or short-term toxicity studies Approval of the authorized IRB Designed to determine the toxic effects if a test 1994: National Institue of Health (NIH) issued its compound when administered in a single dose or in policy that women and minorities be included in all multiple doses over a short period, usually a single NIH-supported research day Purpose of IRB: to protct the safety of human Doses are ranged to find the largest single dose that subjects by assessing a proposed clinical protocol, will not produce a toxic effect evaluate the benefits against risks, and ensuring that 30-day post period the plan includes all needed measures for subject Subacute or subchronic studies protection Minimum of 2 weeks of daily drug administration at Pre-IND Meetings three or more dosage levels to two animal species May include advice on the adequacy of data to Initial human dose is usually one tenth of the highest support an investigational plan, the design of a non toxic dose clinical trial Chronic toxicity studies: 90-180 days FDA Review of an IND Application Carcinogenic Studies Objecttives Undertaken when the compounds has shown o Protect the safety and rights of the human sufficient promise s a drug to enter human clinical subjects trials o Help ensure that the study allows the Long term (18-24 months) evaluation of the drugs safety and Reproduction studies effectiveness o Stamped then sent to the Center for Drug To reveal any effect if an active ingredient on mammalian reproduction Evaluation Research (CDER) or the Center for Biologics Evaluation and Research Rabbit is the preferred choice (CBER) for review Genotoxicity or mutagenicity studies FDA Drug Classification Performed to determine whether the test compound By chemical type of therapeutic potential can affect gene mutation of cause chromosome or Phases of a Clinical Investigation DNA damge Phase 1 Salmonella typhimurium strains are used Initial introduction of the investigational drugs into Purpose: to gain permission to market the drug humans for the purpose of assessing safety product in the US 20 to 100 subjects FDA Review and Action Letters Initial dose is one tenth of the highest no-effect dose Review clock: 180-day period Designed to determine the human pharmacology of the drug, structure-activity relationships, side effects Phase 4 Studies and Postmarketing Surveillance associated with increasing doses and early evidences Phase 4: continued clinical investigations of effectiveness Postmarketing Reporting of Adverse Drug Experience Rate of absorption, concentration of drug in blood 15 working days over time, rate of mechanism Phase 2 Controlled clinical studies to evaluate the effectiveness of a drug in patients with the condition Asses side effects and risks that may be revealed [Supplemental, Abbreviated and other Applications] Additional date on the drugs pharmacokinetics and ANDA dose-response and dose ranging (Phase 2a studies) Nonclinical laboratory studies and clinical Dose determination studies (Phase 2b) investigations may be omitted, except those pertaining to the desired bioavailability Drug product is refined Usually for duplicates Phase 3 [International Conference on Harmonization of Include several hundred to several thousand patients Technical Requirements for Registration of in controlled and uncontrolled trials Pharmaceuticals for Human Use] Objective is to determine the usefulness of the drug Focused on quality, safety and efficacy in an expanded patient base Completed studies (Phase 3a) Additional studies (Phase 3b) Chapter 3: Current Good Manufacturing Practices Clinical Study Controls and Designs Blinded studies and Current Good Compounding Practices Identity of the investigational drug and the control are not revealed [Standards for Current Good Manufacturing Practice] Single blind studies Established by the FDA to ensure that minimum Patient is unaware of the agent administered standards are met for drug product quality Double blind studies [cGMP for Finished Pharaceuticals] Neither the patient nor the clinician is aware or the Active ingredient or active pharmaceutical ingredient (API) agent administered Any component that is intended to furnish Parallel designs pharmacologic activity or other direct effect in the Applicable to most clinical trials diagnosis, prevention of diseases Batch Crossover designs A specific quantity of a drug of uniform specified Useful in comparing different treatments within quality produced according to a single manufacturing individuals order during the same cycle of manufacture Drug Dosage and Terminology Batchwise control Minimum effective concentration (MEC) Use of validated in-process sampling and testing An average blood serum concentration that can be methods expected to produce the drug's desired effects Certification Minimum toxic concentration (MTC) Documented testimony Second level of serum concentration Compliance Median effective dose Determination through inspection Amount that will produce the desired intensity of Component effect in 50% of the individuals tested Therapeutic index Any ingredient used in the manufacture of a drug Relationship between the desired and undesired product Drug product effects of the drug A finished form that contains an active drug and Defined as the ratio between a drugs median toxic inactive ingredients dose and its median effective dose (TD50/ED50) Lot Age Pharmacogenetics A batch Body weight Master record BSA Record containing the formulation, specifications, Sex manufacturing procedures Pathologic state Quality assurance Tolerance Provision to all concerned the evidence needed to Ability to endure the influence of a drug, particularly establish confidence during continued use Quality audit Concomitant drug therapy Documented activity performed in accordance with Effects of a drug may be modified by the prior or established procedures on a planned and periodic concurrent administration of another drug basis Time and conditions of administration Quality control unit Dosage form and route of administration Organizational element designed by a firm Treatment IND Representative sample Permits the use of an investigational drug in the A sample that accurately portrays the whole treatment of patients not enrolled in the clinical Reprocessing study but who have serious or immediately life- Activity whereby the finished product or any of its threatening disease components are recycled [The New Drug Application] Strength Concentration of the drug substance per unit dose or 45 days in solid state volume Low-risk and medium-risk compounding Process validation Involves sterile products an equipment Documented evidence that a process does what it Food and Drug Modernization Act of 1997 purports to do To ensure patients access to individualized drug Validation protocol therapy and prevent unnecessary FDA regulation of A prospective experimental plan to produce health professional practice documented evidence that a system has been A compounded product is exempt if the drug product validated is compounded for an individual patient Expiration Dating Mtdland decision: compounded preparations are not Determined by the appropriate stability testing new drugs National Association of Boards of Pharmacy Subpart (A), General Provisions Tamper-Evident Packaging Compounding means the preparation of Film wrapper Components into a Drug Sealed around product and/or product container; fi Manufacturing means the production, preparation, lm must be cut or torn to remove product propagation, conversion, or processing of a Drug or Blister/strip pack Devices Individually sealed dose units; removal requires Subpart (B), Organization and Personnel tearing or breaking individual compartment Discusses the responsibilities of pharmacists and Bubble pack other personnel engaged in compounding. Product and container sealed in plastic, usually Stresses that only personnel authorized by the mounted on display card; plasticmust be cut or responsible pharmacist shall be in the immediate broken open to remove product vicinity of the drug compounding operation Shrink seal, band Subpart (C), Drug Compounding Facilities Band or wrapper shrunk by heat or drying to conform Describes the areas that should be set aside for to cap; must be torn to open package compounding, either sterile or not Foil, paper, plastic pouch Subpart (D), Equipment Sealed individual packet; must be torn to reach States that equipment used must be of appropriate product design, adequate size, and suitably located to Bottle seal facilitate operation for its intended use Paper or foil sealed to mouth of container under cap; Subpart (E), Control of Components and Drug Product must be torn or broken to reach product Containers and Closures Tape seal Describes the packaging requirements for Paper or foil sealed over carton flap or bottle cap; compounded products. must be torn or broken to reach product Subpart (F), Drug Compounding Controls Breakable cap Discusses the written procedures to ensure that the Plastic or metal tearaway cap over container; must finished products are of the proper identity, strength, be broken to remove quality, and purity, as labeled. Sealed tube Subpart (G), Labeling Control of Excess Products and Records Seal over mouth of tube; must be punctured to reach and Reports product Describes the various records and reports that are Sealed carton required under these guidelines. Carton flaps sealed; carton cannot be opened without [Packaging, Labeling and Storage of Pharmaceuticals] damage Containers Aerosol container That which hold the article and is or may be in direct Tamper-resistant by design contact with the article at all rimes Records and Reports Well-closed container Production, control and distribution documents must Minimally acceptable container be kept for at least one year after expiration Protects the contents from extraneous solids and [Current Good Compounding Practices] from loss of the article US Pharmacopeia-National Formulary Tight container First compounding monographs became official in Protects the contents from contamination by 1998 extraneous liquids, solids or vapors, efflorescence, (Beyond-use dates) deliquescence or evaporation For non aqueous liquids and solid formulations Capable of tight re-closure Where the manufactured drug product is the source Hermetic container of the active ingredient, not later than 25% or 6 Impervious to air or any gas months Sterile hermetic container Where a USP or NF substance is the source, nlt 6 Hold preparations intended for injection months Single-dose container For water-containing formulations Cannot be resealed Nlt 14 days when stored at cold temperatures Fusion-sealed ampules, prefilled syringes and Low-risk preparations at room temp cartridges Nmt 48 hours Glass (Refrigerated) nmt 14 days Type I: highly resistant borosilicate glass Medium-risk at room temp Type II: treated soda lime Nmt 30 hrs Type III: soda lime (Refrigerated) nmt 9 days NP: general purpose soda lime High-risk preparations at room temp Polyvinyl chloride (PVS) Nmt 24 hours Rigid and has good clarity (Refrigerated) nmt 3 days Blister packaging Low, Medium, High-risk s (-25 - -10 degrees C) Unsuitable for gamma sterilization Polyethylene terephthalate (PET), Amorphous polyethylene a dosage form terephthalate glycol (APET), polyethylene terephthalate glycol Physical Description (PETG) Particle size, crystalline structure, melting point and Permeability solubility Process of solution and diffusion Microscopic Examination Glass are less permeable than plastic Gives an indication of particle size and size range of Humidity the raw material along with the crystal structure Test for a minimum of 12 months at 25 degrees C Heat of Vaporization Desiccants The amount of heat absorbed when 1g of a liquid Oxidation vaporizes Greater degree in plastic than in glass Measured in calories Leaching Melting Point Depression Movement of components of a container into the Characteristic of a pure substance contents Temperature at which the pure liquid and solid exist Soft-walled plastic containers of PVC: IV solutions for in equilibrium blood transfusion The Phase Rule Sorption Two-component (binary) or three-component Binding of molecules to polymer materials representations Child-resistant and Adult-Senior Use Packaging Represent the melting point as a function of Potson Prevention Act composition of two or three systems Reduce accidental poisoning through ingestion of Particle Size drugs Polymorphism Child-resistant containers (5 years and below) Exhibit different physiochemical properties Align the arrows, press down and turn, squeeze and Solubility turn, latch top Determined by the equilibrium solubility method Storage Solubility and pH Cold Dissolution 8 degrees C Time it takes for the drug to dissolve Cool May be increased by decreasing the drugs particle 8-15 degrees C size Warm Constant surface method 30-40 degrees C o Uses a compressed disc of known area o Eliminate surface are and surface electrical Chapter 4: Dosage Form Design: Pharmaceutical charges as dissolution variables Formulation Considerations o Intrinsic dissolution rate o Mg dissolved per minute per cm squared Pharmaceutical ingredients Membrane Permeability Nonmedicinal agents Early assessment of passage of drug molecules [The Need for Dosage Forms] across biologic membranes To protect the drug substance from the destructive Partition Coefficient influences of atmospheric oxygen or humidity Measure of a molecules lipophilic character (coated tablets, sealed ampules) pKa/Dissociation Constants To protect the drug substance from the destructive Drug and Drug Product Stability influence of gastric acid after oral administration Drug Stability Mechanisms of Degregation (enteric-coated tablets) Hydrolysis: solvolysts process in which drug To conceal the bitter, salty, or offensive taste or odor molecules interact with water molecules to yield of a drug substance (capsules, coated tablets, breakdown products flavored syrups) Oxidation To provide liquid preparations of substances that are Autoxidation: occur spontaneously under the initial either insoluble or unstable in the desired vehicle influence of atmospheric oxygen and proceed slowly (suspensions) at first then more rapidly To provide clear liquid dosage forms of substances Drug and Drug Product Stability: Kinetics and Shelf Life (syrups, solutions) Stability: extent to which a product retains within To provide rate-controlled drug action (various specified limits and throughout its period of storage controlled-release tablets, capsules, and and use the same properties and characteristics that suspensions) it possessed at the time of its manufacture To provide optimal drug action from topical Chemical, physical, microbiologic, therapeutic, administration sites (ointments, creams, transdermal toxicologic patches, and ophthalmic, ear, and nasal Reaction kinetics: study of the rate of chemical preparations) change and the way this rate is influenced y To provide for insertion of a drug into one of the concentration of reactants bodys orifices (rectal or vaginal suppositories) Rate Reactions To provide for placement of drugs directly in the Description of the drug concentration with respect to bloodstream or body tissues (injections) time Q10 Method of Shelf Life Estimation To provide for optimal drug action through inhalation therapy (inhalants and inhalation aerosols) Lets the pharmacist estimate shelf life [General Considerations in Dosage Form Design] Enhancing Stability of Drug Products Master formula Reduction or elimination of water Formulation that best meets the goals for the product Anhydrous vegetable oils may be used to reduce the Systemic use: oral administration chance of hydrolytic decomposition in injectable Preformulation Studies Decomposition by hydrolysis may be prevented in Provides the framework for the drugs combination other liquid drugs by suspending them in a with pharmaceutical ingredients in the fabrication of nonaqueous vehicle Reconstitution Area of study that elucidates the time course of drug Antioxidants concentration in the blood and tissues (ADME) o Aqueous: sodium sulfite, sodium bisulfite, Metabolism sodium metabisulfite, hypophosphorous Major process by which foreign substances are acid, ascorbic acid eliminated from the body o Oleaginous preparations: alpha-tocopherol, Principles of Drug Absorption butyl hydroxyl anisole, ascorbyl palmitate Passive Diffusion Trace metals Passage of drug molecules through a membrane that Polymerization (two or more identical molecules that does not actively participate in the process form a new and generally larger molecule), chemical High to low concentration decarboxylation and deamination Ficks Law: the rate of diffusion or transport across a Stability Testing membrane is proportional to the difference in drug Accelerated stability testing concentration on both sides of the membrane o Use of exaggerated conditions of First-order kinetics temperature, humidity, light and others pK: pH at which a drug is 50% ionized Specialized Transport Mechanisms Active: lower to higher concentration [Pharmaceutical Ingredients and Excipients] [Dissolution and Drug Absorption] Definitions and Types Diffusion layer: layer of solution Solvents Dissolution rate of a drug may be increased by Used to dissolve the drug substance increasing the surface area (reducing particle size) Flavors and sweeteners Crystal or Amorphous Drug Form Used to make the product more palatable Amorphous form of a chemical is usually more Colorants soluble than the crystalline form Enhance appeal Novoviocin and chloramphenicol palminatate are Preservatives inactive when administered in crystalline form but is Prevent microbial growth active in amorphous form Diluents or fillers Penicillin: crystalline form > amorphous form For tablets Salt Forms Increase bulk of formation Addition of ethylenediamine to theophylline Binders increases the water solubility of theophylline fivefold Cause adhesion of the powdered drug and [Bioavailability and Bioequivalence] pharmaceutical substances Bioavailability Antiadherents/lubricants Rate and extent to which an active drug ingredient or Smooth tablet formation therapeutic moiety is absorbed from a drug product Disintegrating agents and becomes available at the site of action Promote tablet breakup Depends on the drugs absorption or entry in the Handbook of Pharmaceutical Excipients and Food and systemic circulation Chemicals Codex Bioequivalence Handbook of Pharmaceutical Excipients Comparison or bio availabilities of different More than 250 excipients formulations, drug products or batches of the same Appearance and Palatability drug product Flavoring Pharmaceuticals Used to determine the amount or proportion of drug Increase in the number of hydroxyl groups seems to absorbed, the rate at which the drug was absorbed. increase the sweetness Duration of the drugs presence in the biologic fluid Sweetening Pharmaceuticals or tissue correlated with the patients response, Aspartame, saccharin and cyclamate relationship between drug blood levels and clinical Delaney Clause: no new food additive may be used if efficacy and toxicity animal feeding studies or tests showed that it caused [Routes of Drug Administration] cancer Local effects: direct contact of the drug to the site of Saccharin Study and Labeling Act action Coloring Pharmaceuticals Systemic effect: entrance of the drug into the Sulfur (yellow), riboflavin (yellow), cupric sulfate circulatory system and transport to the cellular site (blue), ferrous sulfate (bluish green), cyanocobalamin of its action (red), red mercuric iodide (vivid red) Bioavailability is lowest for drugs that undergo a Coal tar: black significant first-pass effect Preservatives Oral Route Sterilization and Preservation Systemic drug effects 15% V/V alcohol will prevent microbial growth in acid Most natural, uncomplicated, convenient and safe media, 18% in alkaline media means of administering drugs Preservative Selection Disadvantages: slow drug response, destruction of Cellulose derivatives: polyethylene glycols, natural certain drugs by the acid reaction of the stomach gums: tragacanth Dosage forms applicable Tablets Chapter 5: Dosage Form Design: o Prepared by compression or molding that Biopharmaceutical and Pharmacokinetic contains medicinal substances Considerations o Diluents are fillers used to prepare tablets o Disintegrants are used for the breakup or Biopharmaceutics separation o Enteric coatings: safe passage through the Relationship between the physical, chemical and acid environment biologic sciences as they apply to drugs, dosage forms and drug action Capsules Pharmacokinetics o Enclosed in either a hard or soft shell, generally composed of gelatin Forearm, upper arm, thigh or buttocks Suspension Intramuscular Injections o Finely divided drugs in a suitable fluid Aqueous or oleaginous solutions or suspensions vehicle Intravenous Injections o Drug particles must be suspended in an Injected directly into the vein insoluble vehicle Intradermal Injections o Useful means to administer large amounts Administered into the corium of the skin (0.1mL) of solid drugs Epicutaneous Route Solution Topically Elixir Nitroglycerin (antianginal), nicotine (smoking o Solutions in a sweetened hydroalcoholic cessation), estradiol (estrogenic hormone), clonidine vehicle (antihypertensive), and scopolamine (antinausea, Syrups antimotion sickness) o Use sucrose solution Local action Absorption Ointments Sublingual: with nitroglycerin and certain steroid sex o Simple mixtures of drug substances in an hormones ointment base Tetracycline drugs must not be taken with milk Creams Rectal Route o Semisolid emulsions les viscid and lighter Suppositories than ointments o Promotion of laxation, soothing of inflamed Pastes tissues, promotion of systemic effcts o Stiffer and less penetrating Parenteral Route o Employed for its protective action Para = beside Medicinal powder Enteron = intestine o Relieves diaper rash, chafing, and athletes Dosage Forms Applicable foot Slow absorption = prolonged drug action; Lotions subcutaneous or IM: depot or repository injection o Emulsions or suspensions generally in an Subcutaneous (Hypodermic) Injections aqueous vehicle Injection through the skin into the loose o Nongreasy subcutaneous tissue Ocular, Oral, Otic and Nasal Routes Insulin Local effects\ More capillaries = more surface are for absorption = faster rate of absorption
Notice: Human Drugs: Drug Products Withdrawn From Sale For Reasons Other Than Safety or Effectiveness— Celestone Soluspan Injection and Celestone Injection